Alzheimer Disease (AD) is a progressive brain disease known generally as senile dementia. More than 4.5 million Americans have been diagnosed with AD, and this number is expected to triple in the next 40-50 years. There is currently no cure for AD. The treatments available today for AD are symptomatic and do not interfere with inexorable progression of the underlying disease process. There is a desperate need for interventions that might improve symptoms and modify the disease progression. The two defining neuropatholic features of AD are abnormal aggregation and deposition of A2 peptides and tau in the brain as, respectively, extracellular neuritic plaques (NP) and intracellular neurofrillary tangles (NFT). In the brain, monomeric Ab peptides and tau proteins are aggregated to form high molecular weight, soluble multimeric neurotoxic Ab and tau species. Continual progressive aggregations of multimeric Ab and tau species result in deposition of Ab and tau into, respectively, NP and NFT. Recent experimental evidence indicates that it is the accumulation of soluble high- molecular weight (HMW) oligomeric A2 and tau species in the brain, rather than deposition of NP and NFT per se, may be specifically related to cognitive dysfunction in AD. We recently demonstrated that a select grape- seed polyphenol extract (GSPE), namely, MegaNatural-Az(R) GSPE to potently inhibit the aggregation of both Ab peptides and tau proteins. Thus, MegaNatural-Az(R) GSPE may benefit AD by mitigating both Ab- and tau- mediated neurotoxic responses. Based on this and evidence demonstrated the high tolerability and safety of long-term application of MegaNatural-Az(R) in both laboratory animals and in human. The proposed study represents collaboration between basic science research laboratories and the Alzheimer's Disease Clinical Core at the Mount Sinai School of Medicine to explore the development of MegaNatural-Az(R) for treating AD. In particular, our proposed study will establish safety and pharmacokinetics of Meganatural-Az(R) GSPE in AD subjects. As secondary measures, we will also evaluate clinical and biomarker indexes of therapeutic efficacy. The proposed study will provide the essential human data to guide the design of future studies to test the efficacy of GSPE in mitigating cognitive deterioration in AD patients. PUBLIC HEALTH RELEVANCE: This is an application to study the feasibility of developing a select grape seed extract, referred to as MegaNatural- Az (R) for treating Alzheimer's Disease. Meganatural -AZ (R) has been shown to benefit AD phenotypes in experimental in vitro and animal AD model systems by potently interfering with aggregation of beta-amyloid peptides and tau proteins into neurotoxic aggregates. The study will access safety, pharmacokinetics of MegaNatural- Az (R) in AD patients and explore cognitive and biological indices of therapeutic efficacy in a 10 week multiple dose escalation study.